期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 4, 页码 1081-1092出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20162011
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资金
- National Institute of Neurological Disorders and Stroke [P30 NS079375-01A1, R35 NS097976]
- Alexander von Humboldt Foundation
- Kirschstein National Research Service Award predoctoral fellowship
- Jane Coffin Childs Memorial Fund for Medical Research
- John Douglas French Alzheimer's Foundation
- National Institutes of Health/National Institute on Aging [R01 AG042513]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [P01 NS074969]
- Paul F. Glenn Center for the Biology of Aging
- Department of Veterans Affairs
- National Institute on Aging [AG045034]
Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble beta-amyloid (A beta) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, A beta accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular A beta by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble A beta levels and A beta half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits A beta clearance from the ISF, illustrating a novel role for CR3 and microglia in brain A beta metabolism and defining a potential new therapeutic target in AD.
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